Interferon-β regulates cytokines and BDNF: greater effect in relapsing than in progressive multiple sclerosis

Abstract

The mechanism of action of interferon (IFN)-β therapy in multiple sclerosis (MS) is only partially known, and its efficacy changes with disease stage. In different forms of MS, we determined how IFN-β regulates mononuclear cell production of the important anti-inflammatory Th2 cytokine - IL-10, the Th1 cytokine - IFN-γ, and the brain-derived neurotrophic protein - BDNF. Activated T cells and monocytes from therapy-naïve patients secreted more IL-10 than healthy controls. During IFN-β therapy, however, T cells produced less IL-10. In vitro, IFN-β stimulated IL-10 production by activated T cells, but inhibited IL-10 secretion by activated monocytes, a richer source of IL-10 than T cells. The form of MS also affected cytokine production. IL-10 and BDNF levels in MNC were high during relapsing/remitting (RR) MS, but low in progressive MS. Surprisingly, IFN-β therapy increased BDNF levels in antidepressant-naïve patients, but BDNF was lower during concurrent antidepressant drug therapy, suggesting an interaction between MS, depression, and neurodegeneration. IFN-β in vitro strongly induced IL-10 and IFN-γ in activated T cells in RRMS, but not in progressive MS, suggesting IFN resistance. IFN-β effects are specific for disease state and immune subsets, possibly explaining why IFN-β therapy is most effective in early T cell-regulated RRMS, but less beneficial in progressive MS, where chronic plaques contain few T cells and high numbers of monocytes. Multiple Sclerosis 2007; 13: 459-470. http://msj.sagepub.com